The present invention relates to an implantable device for delivering a preselected molecule into systemic circulation. More particularly, this invention relates to an implantable device containing viable cells. When the device is implanted into a blood vessel, the cells produce and secrete the preselected molecule into blood circulating past the device.
The development of drug delivery devices for implantation into a pre-selected locus in a mammal is ongoing. To date, a variety of surgically implantable drug delivery devices have been developed and are discussed below.
U.S. Pat. No. 4,378,016 describes a surgically implantable device for delivering an active factor, for example, a hormone, to a pre-selected site, for example, the peritoneal cavity, of a mammal. The device comprises a fluid permeable membranous sack for implantation within the mammal and an impermeable hollow tube having one end connected to an opening in the sack and the other end designed to remain outside the body of the mammal. The tube provides an access passageway to the membranous sack, such that after the sack has been surgically implanted into the mammal, a cell containing envelope may be introduced into the sack via the tube. Upon insertion of the cell containing envelope into the sack, the cells may produce an active factor, which subsequently may diffuse into the surrounding tissue or organ of the recipient.
U.S. Pat. No. 5,182,111 describes a surgically implantable device for delivering an active factor to a pre-selected site, for example, a tissue or organ, in a mammal. The device comprises a semi-permeable membrane enclosing at least one cell type that produces a specific active-factor and a second cell type that produces an augmentory factor. The augmenting factor produced by the second cell type subsequently induces the first cell type to produce the active-factor.
U.S. Pat. No. 4,479,796 describes a surgically implantable dispenser for infusing a pre-selected drug directly into the blood stream. Briefly, the dispenser is surgically spliced in line with a blood vessel. The dispenser encloses a replaceable cartridge of cells, for example, micro-organisms, which produce and secrete the drug into blood flowing past the cartridge.
U.S. Pat. No. 4,309,776 describes an intravascular drug delivery device having a chamber containing transplanted cells for surgical implantation into the wall of a blood vessel. The device comprises a porous wall that permits a hormone produced by the transplanted cells to diffuse out of the chamber and into the blood stream.
It is desirable, however, to produce a device that may be implanted into a mammal by either non-surgical or only minimally invasive surgical procedures, and that once implanted the device secretes a pre-selected molecule directly into the vasculature. In addition, it is desirable to produce a device which, when implanted, administers the pre-selected molecule into the mammal over an extended period and may be removed conveniently, if or whenever the necessity arises. Accordingly, it is an object of the present invention to provide an easily implantable device for delivering, over long periods of time, a pre-selected molecule into the systemic circulation of a mammal. It is another object to provide a method for non-surgically implanting the device into a blood vessel of a mammal for delivering the pre-selected molecule into systemic circulation.
These and other objects and features of the invention will be more clearly understood from the description, drawings, and claims which follow.
The present invention provides an implantable device for delivery of a pre-selected molecule into the systemic circulation of a mammal. The device of the invention may be implanted using non- or minimally invasive surgical procedures and, once implanted, delivers the preselected molecule directly into the blood stream. In addition, the device of the invention is adapted to produce in situ and thereafter secrete the pre-selected molecule into the blood stream over a prolonged period of time. Use of the present device and method provides an easy and reproducible system for delivering therapeutically effective amounts of a gene product, for example, a hormone, growth factor, anti-coagulant, immunomodulator, cytoldne, or the like, directly into the blood stream of the recipient. The devices of the present invention, although having a variety of utilities, are particularly suited for use in hormone replacement therapy.
In its broadest aspect, the device comprises a blood permeable element, which is adapted for anchorage to an inner surface of a blood vessel. The blood permeable element, as disclosed herein, is designed such that when anchored to the inner surface of the blood vessel, the element permits blood in the vessel to pass therethrough. The device further comprises a capsule that may be positioned, and retained in place, by contacting the element disposed within the vessel. The capsule contains viable cells which produce and secrete the pre-selected molecule into the blood stream.
The term xe2x80x9csystemic circulationxe2x80x9d as used herein is understood to embrace any blood vessel within a mammal, i.e., an artery, arteriole, venule or vein, that provides a blood supply to all tissues, except lung tissues perfused by the pulmonary circulation, of a mammal. The systemic circulation is also referred to in the art as the greater circulation or the peripheral circulation.
The term xe2x80x9cblood permeable elementxe2x80x9d as used herein is understood to mean any structure for insertion into the lumen of a blood vessel in the systemic circulation that, once inserted, may be anchored, for example, by hooks or barbs, to an inner surface of the blood vessel. The element being further characterized in that when anchored to the inner wall of the blood vessel, the element does not occlude or prevent blood flow through the blood vessel.
In a preferred embodiment, the blood permeable element is an embolism anti-migration filter, such as a blood clot anti-migration filter. A variety of blood clot anti-migration filters useful in the practice of the invention are known in the art. The currently preferred blood permeable element is an anti-migration filter known as a xe2x80x9cGreenfield(copyright) vena cava filterxe2x80x9d. Useful Greenfield(copyright) vena cava filters are described in detail in U.S. Pat. Nos. 4,817,600 and 5,059,205, the disclosures of which are incorporated by reference herein.
The term xe2x80x9ccapsulexe2x80x9d as used herein is understood to mean any hollow structure dimensioned to fit within the lumen of a blood vessel, which, when introduced into the blood vessel, does not occlude or prevent blood flow through the vessel. The capsule is held in place within the blood vessel by means of the blood permeable element. For example, the capsule may be retained upstream of the blood permeable element when the capsule is of a size such that it cannot pass through the blood permeable element. Alternatively, the blood permeable may be located downstream of the blood permeable element but retained in place by an attachment means, for example, a hook or tether, extending from the blood permeable element to the capsule. In addition, it is contemplated that the capsule may be wedge-like in shape, such that the narrow end of the wedge may pass through the element but the larger end contacts the element thereby to prevent passage of the capsule through the element.
The capsule may comprise either a single hollow fiber or a bundle of hollow fibers made from a semi-permeable membrane. The semi-permeable membrane preferably has pores of a size sufficient to permit the diffusion of the preselected molecule therethrough but yet small enough to exclude the passage of cells therethrough. The pores preferably are designed to permit the preselected molecule produced by the cells to diffuse directly into the blood stream passing the hollow fiber while preventing the cells from migrating out of the hollow fiber and into the systemic circulation. More specifically, the pores preferably are dimensioned to allow solutes having a molecular weight of less than about 150 kilo daltons to pass therethrough while excluding agents in the blood stream, for example, proteins, specifically, antibodies and cytolytic factors secreted by lymphocytes, or cells, specifically, macrophages and lymphocytes, which if allowed to pass though the pores from the blood stream into the hollow fiber may be detrimental to the viability of the cells enclosed therein. It is contemplated that if the preselected molecule has a molecular weight greater than about 150 kilo daltons then the capsule should have pores dimensioned to permit the preselected molecule to diffuse out of the capsule into the blood stream. It should be noted, however, that the viable cells useful in producing and secreting preselected molecules having a molecular weight greater than 150 kilo daltons should be autologous in nature thereby minimizing a host immune response, humoral and/or cellular, directed against the cells disposed within the capsule.
Polymers useful in producing biocompatible semi-permeable membranes of the present invention include, but are not limited to, polyvinylchloride, polyvinylidene fluoride, polyurethane isocyanate, polyalginate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose nitrate, polysulfone, polystyrene, polyurethane, polyvinyl alcohol, polyacrylonitrile, polyamide, polymethylmethacrylate, polyethylene oxide and polytetafluoroethylene. In addition, it is contemplated that useful semi-permeable membranes may be produced from a combination of such polymers.
In another preferred embodiment, the viable cells enclosed within the semi-permeable hollow fiber(s) of the capsule, preferably are eukaryotic cells, and most preferably are mammalian cells. Although, the device described herein may comprise cells which naturally produce and secrete the preselected molecule, it is contemplated that genetically engineered cells, ie., cells transfected with, and capable of expressing a nucleic acid encoding the pre-selected molecule, may likewise be used in the practice of the invention.
In another preferred embodiment, the preselected molecule preferably is a protein, and most preferably is a hormone, for example, erythropoietin or insulin. It is contemplated, however, that the device may be used to deliver into the systemic circulation any molecule that can be produced and secreted from a viable cell. Although single cell types that produce and secrete a single preselected molecule may be used in the invention, it is understood that cells belonging to a particular cell type that produce and secrete a plurality of pre-selected molecules likewise may be used in the practice of the instant invention. Similarly, it is contemplated that a plurality of cell types, wherein cells belonging to each cell type produce and secrete different preselected molecules, may be combined in a capsule thereby to produce a device that delivers a desirable combination of preselected molecules into the circulation.
In some applications, for example, during hormone replacement therapy, it is preferable to use cells which produce the preselected molecule in response to an external stimulus. A device containing such regulated cells therefore produces the pre-selected molecule when the necessity arises thereby preventing an overproduction of the preselected molecule, which, depending upon the molecule, may be detrimental to the recipient. However, during other applications, for example, during replacement therapy of Factor VIII in Factor VIII deficient hemophilia; Factor IX in Factor IX deficient hemophilia; or xcex11-anti-trypsin in xcex11-anti-trypsin deficient emphysema, it is contemplated that cells which constitutively produce these preselected molecules, may be enclosed in the hollow fibers of the device.
Certain forms of anemias, for example, erythropoietin deficient anemias caused by end stage renal disease, result from the inability of the host to produce erythropoietin in an amount sufficient to induce the production of sufficient numbers of red blood cells. As a result of this disease, the patient""s red blood cell mass falls thereby lowering the oxygen carrying potential of the blood. In one preferred embodiment, the invention therefore provides a device comprising erythropoietin producing cells that produce erythropoietin in response to the reduced oxygen carrying capacity of the recipient""s blood. The invention permits the erythropoietin producing cells to be exposed to blood intimately enough so that full endocrine function of the cells can be realized effectively. Accordingly, it is contemplated that the implantable erythropoietin producing and secreting device of the invention may be useful in the treatment of erythropoietin deficient anemias.
In addition, certain forms of diabetes, for example, diabetes mellitus, result from an inability of the host to produce insulin in an amount sufficient to modulate the level of circulating glucose in the blood stream. In another preferred embodiment, the invention provides a device comprising insulin producing cells that produce insulin in response to the level of glucose in the blood. Accordingly, it is contemplated that the implantable insulin producing and secreting device of the invention may be useful in the treatment of insulin dependant forms of diabetes.
In another aspect, the invention provides a method for percutaneously introducing into a blood vessel of a mammal, a device for delivering a pre-selected molecule into systemic circulation. The method comprises the steps of: (a) anchoring a blood permeable element to an inner wall of an intact blood vessel, which when anchored permits blood in the vessel to pass therethrough; (b) introducing at a location upstream of the anchored element a capsule containing viable cells that produce and secrete the preselected molecule; and (c) permitting the capsule to contact the element.
In this procedure, the blood permeable element may be introduced into the blood vessel by means of a catheter. Furthermore, the capsule may likewise be introduced into the vessel by means of the same or a different catheter. During such procedures the blood permeable element and/or the capsule may be introduced by a catheter into the mammal via a femoral or jugular vein and then anchored in a natural vein, for example, an inferior vena cava, a superior vena cava, a portal vein or a renal vein, or alternatively, anchored in a synthetic vein, for example, a vein developed from a surgically-eveloped arteriovenous fistula. It is contemplated that selection of appropriate sites for introduction and anchorage of the device is within the expertise of one skilled in the art.